Body Mass Index Modifies the Risk of Cardiovascular Death in Proteinuric Chronic Kidney Disease
Body Mass Index Modifies the Risk of Cardiovascular Death in Proteinuric Chronic Kidney Disease
Background. In subjects with end-stage renal disease, a high body mass index (BMI) is inversely related to overall mortality, which has been coined reverse epidemiology phenomenon. This study sought to investigate this paradox as well as a possible risk modification by proteinuria on the relationship of BMI with earlier stages of chronic kidney disease (CKD) concerning cardiovascular mortality.
Methods. We used the Vienna Health Screening Initiative, a longitudinal cohort study from 1990 to 2006, including 49 398 volunteers (49.9% women, age 20–89 years): n = 2487 showed mild CKD (proteinuria and GFR > 60 ml/min/1.73 m) and n = 392 showed moderate CKD (GFR = 30–59 ml/min/1.73 m). The follow-up period was 5.5 ± 4.2 years; n = 148 cardiovascular deaths occurred. Exposure variables were BMI, glomerular filtration rate (GFR) and proteinuria. Cox regression models on cardiovascular mortality with adjustment for age, sex, log(cholesterol/HDL), uric acid, smoking, glucose, diabetes, mean blood pressure, hypertension and antihypertensive drug use were fitted.
Results. The risk factor paradox is shown in moderate CKD (GFR = 45 ml/min/1.73 m): hazard ratios (HR) of BMI contrasts decreased consistantly from 1.28 (95% CI 0.33–5.82) at BMI 20 kg/m versus 25 kg/m to 0.76 (95% CI 0.38–1.50) at BMI 30 kg/m versus 25 kg/m and to 0.58 (95% CI 0.13–2.64) at BMI 35 kg/m versus 25 kg/m, thus showing an inverse relationship compared to mild CKD/healthy participants. Examining proteinuria as an effect modifier in this context showed that in moderate CKD (contrast: proteinuria versus no proteinuria) HR decreased more profoundly from 9.43 (95% CI 2.66–27.40) at BMI 25 kg/m to 3.74 (95% CI 0.93–15.70) at BMI 30 kg/m and to 1.95 (95% CI 0.37–22.30) at BMI 35 kg/m, and conversely in non-proteinuric subjects, hazards for cardiovascular mortality increased in underweight as well as in overweight/obese subjects in a U-shaped manner.
Conclusions. Our results suggest that obese subjects with proteinuric CKD may not be counselled for weight reduction since a higher BMI was associated with a remarkably reduced risk of death.
Subjects with chronic kidney disease (CKD) or end-stage renal disease (ESRD) have a dramatically increased risk of cardiovascular and overall mortality. Interestingly, traditional key risk factors for cardiovascular disease in the general population such as obesity, hypercholesterolaemia and hypertension are inversely related to mortality in haemodialysis patients. This paradox has been coined 'risk factor reversal' or 'reverse epidemiology phenomenon'.
In fact, it has been shown in the largest international prospective cohort study of 16 720 haemodialysis patients followed up for 5 years that irrespective of race, gender, severity of comorbidities, age, smoking and diabetic status, obesity is associated with a reduced risk of death.
Moreover, mild to moderate renal insufficiency was shown to be associated with elevated long-term risk of cardiovascular and overall death adjusted for several covariables. The question of effect modification by body mass index (BMI) in earlier stages of CKD has been investigated in several studies: a higher BMI was associated with a higher prevalence of the metabolic syndrome, but even when adjusted for the factors of the metabolic syndrome, cardiovascular comorbidities and inflammation parameters a higher BMI was associated with a better overall survival in moderate CKD. Another study revealed that after adjustment for case mix and surrogate parameters of the malnutrition–inflammation–cachexia syndrome this inverse association was still present in patients with CKD not yet on dialysis. These findings are supported by a study where a low BMI was related to a greater mortality rate in the same context.
Other studies could not boundlessly confirm these findings: higher BMI and waist circumference were associated with a higher incidence of coronary heart disease among people with CKD. In a cohort including rather young subjects with nondiabetic CKD, BMI did not appear to be an independent predictor of cardiovascular and overall mortality.
Apart from these studies, waist–hip ratio was shown to be associated with incident CKD and mortality, whereas a higher BMI appeared protective for this outcome.
In advanced CKD, protein–energy wasting that appears in ~20–50% of these patients is an important comorbid condition that predicts a poor clinical outcome. It appears that the common pathway for several metabolic derangements is related to exaggerated protein degradation relative to protein synthesis.
Concerning markers of body composition, a higher BMI rather reflects both higher fat and higher muscle mass, whereas an elevated waist–hip ratio better represents the amount of visceral body fat. Keeping in mind the high prevalence of the protein–energy wasting that is strongly associated with poor clinical outcomes in CKD, this study sought to elucidate whether proteinuria might be an effect modifier of the relationship between BMI and cardiovascular mortality in CKD. Additional protein loss due to proteinuria might be tolerated better in patients with a higher BMI, because a higher protein reserve might lead to a more favourable outcome in this context.
Therefore, we analysed the effects of BMI, GFR and proteinuria as well as their interactive effects on cardiovascular mortality in earlier stages of CKD, and we selected patients with mild to moderate CKD using the database of the Vienna Health Screening Initiative.
Abstract and Introduction
Abstract
Background. In subjects with end-stage renal disease, a high body mass index (BMI) is inversely related to overall mortality, which has been coined reverse epidemiology phenomenon. This study sought to investigate this paradox as well as a possible risk modification by proteinuria on the relationship of BMI with earlier stages of chronic kidney disease (CKD) concerning cardiovascular mortality.
Methods. We used the Vienna Health Screening Initiative, a longitudinal cohort study from 1990 to 2006, including 49 398 volunteers (49.9% women, age 20–89 years): n = 2487 showed mild CKD (proteinuria and GFR > 60 ml/min/1.73 m) and n = 392 showed moderate CKD (GFR = 30–59 ml/min/1.73 m). The follow-up period was 5.5 ± 4.2 years; n = 148 cardiovascular deaths occurred. Exposure variables were BMI, glomerular filtration rate (GFR) and proteinuria. Cox regression models on cardiovascular mortality with adjustment for age, sex, log(cholesterol/HDL), uric acid, smoking, glucose, diabetes, mean blood pressure, hypertension and antihypertensive drug use were fitted.
Results. The risk factor paradox is shown in moderate CKD (GFR = 45 ml/min/1.73 m): hazard ratios (HR) of BMI contrasts decreased consistantly from 1.28 (95% CI 0.33–5.82) at BMI 20 kg/m versus 25 kg/m to 0.76 (95% CI 0.38–1.50) at BMI 30 kg/m versus 25 kg/m and to 0.58 (95% CI 0.13–2.64) at BMI 35 kg/m versus 25 kg/m, thus showing an inverse relationship compared to mild CKD/healthy participants. Examining proteinuria as an effect modifier in this context showed that in moderate CKD (contrast: proteinuria versus no proteinuria) HR decreased more profoundly from 9.43 (95% CI 2.66–27.40) at BMI 25 kg/m to 3.74 (95% CI 0.93–15.70) at BMI 30 kg/m and to 1.95 (95% CI 0.37–22.30) at BMI 35 kg/m, and conversely in non-proteinuric subjects, hazards for cardiovascular mortality increased in underweight as well as in overweight/obese subjects in a U-shaped manner.
Conclusions. Our results suggest that obese subjects with proteinuric CKD may not be counselled for weight reduction since a higher BMI was associated with a remarkably reduced risk of death.
Introduction
Subjects with chronic kidney disease (CKD) or end-stage renal disease (ESRD) have a dramatically increased risk of cardiovascular and overall mortality. Interestingly, traditional key risk factors for cardiovascular disease in the general population such as obesity, hypercholesterolaemia and hypertension are inversely related to mortality in haemodialysis patients. This paradox has been coined 'risk factor reversal' or 'reverse epidemiology phenomenon'.
In fact, it has been shown in the largest international prospective cohort study of 16 720 haemodialysis patients followed up for 5 years that irrespective of race, gender, severity of comorbidities, age, smoking and diabetic status, obesity is associated with a reduced risk of death.
Moreover, mild to moderate renal insufficiency was shown to be associated with elevated long-term risk of cardiovascular and overall death adjusted for several covariables. The question of effect modification by body mass index (BMI) in earlier stages of CKD has been investigated in several studies: a higher BMI was associated with a higher prevalence of the metabolic syndrome, but even when adjusted for the factors of the metabolic syndrome, cardiovascular comorbidities and inflammation parameters a higher BMI was associated with a better overall survival in moderate CKD. Another study revealed that after adjustment for case mix and surrogate parameters of the malnutrition–inflammation–cachexia syndrome this inverse association was still present in patients with CKD not yet on dialysis. These findings are supported by a study where a low BMI was related to a greater mortality rate in the same context.
Other studies could not boundlessly confirm these findings: higher BMI and waist circumference were associated with a higher incidence of coronary heart disease among people with CKD. In a cohort including rather young subjects with nondiabetic CKD, BMI did not appear to be an independent predictor of cardiovascular and overall mortality.
Apart from these studies, waist–hip ratio was shown to be associated with incident CKD and mortality, whereas a higher BMI appeared protective for this outcome.
In advanced CKD, protein–energy wasting that appears in ~20–50% of these patients is an important comorbid condition that predicts a poor clinical outcome. It appears that the common pathway for several metabolic derangements is related to exaggerated protein degradation relative to protein synthesis.
Concerning markers of body composition, a higher BMI rather reflects both higher fat and higher muscle mass, whereas an elevated waist–hip ratio better represents the amount of visceral body fat. Keeping in mind the high prevalence of the protein–energy wasting that is strongly associated with poor clinical outcomes in CKD, this study sought to elucidate whether proteinuria might be an effect modifier of the relationship between BMI and cardiovascular mortality in CKD. Additional protein loss due to proteinuria might be tolerated better in patients with a higher BMI, because a higher protein reserve might lead to a more favourable outcome in this context.
Therefore, we analysed the effects of BMI, GFR and proteinuria as well as their interactive effects on cardiovascular mortality in earlier stages of CKD, and we selected patients with mild to moderate CKD using the database of the Vienna Health Screening Initiative.
